Genetics of heart defects and neurodevelopment disorders linked

Congenital heart disease (CHD) is the most common of all birth defects; severe forms used to be fatal, but can now can be surgically corrected in most newborns. However, while many children go on to lead healthy lives, a significant number develop disabling cognitive and social problems.

A massive, multi-institutional project that analyzed all genes from more than 1200 CHD patients and their parents has identified new mutations that contribute to the disease. The researchers were surprised, however, when the results showed that some of the gene mutations linked to severe CHD were also associated with later neurodevelopmental problems such as autism.

“These results indicate that some genes, in particular a class called chromatin modifiers which influence gene expression, are required for both normal heart and brain function, and that a single mutated gene in this class can result in problems in both organs,” said Richard Lifton, Sterling Professor and chair of the Department of Genetics at Yale and co-senior author of the paper published online Dec. 3 in the journal Science.

The study was led by Lifton, a Howard Hughes Medical Institute investigator, and Martina Brueckner, professor of pediatrics and genetics at Yale, along with colleagues at Harvard, Columbia, University of Pennsylvania, and Icahn School of Medicine at Mt. Sinai.

About 40% of children born with severe congenital heart defects go on to develop cognitive or social abnormalities such as autism. It had been unclear whether these neurodevelopmental disabilities were caused by lack of oxygen delivery to the brain, a complication of corrective surgery, or underlying biological mechanisms.

“The similarities in the genetics of CHD and neurodevelopmental disorders are a real surprise,” said Matthew State, chair of psychiatry at University of California-San Francisco, an expert in autism genetics, who was not an author of the current study. “Genetic testing of CHD patients at birth affords the potential to identify infants at very high risk of neurodevelopmental disorders, allowing development of approaches to mitigate adverse outcomes.”

Samir Zaidi of Yale was co-first author of the study, which was funded by the National Institutes of Health.